The long-term goal of our research is to understand, in molecular terms, how cell-to-cell interactions through cell-surface receptors regulate cellular activity, with a particular emphasis on the role of protein tyrosine phosphorylation and dephosphorylation by protein tyrosine phosphorylation and dephosphorylation. Protein tyrosine phosphorylation by protein tyrosine kinases (PTKases) pays a prominent role in the regulation of cell growth, proliferation, differentiation, and development. Disturbance of this process is known to be a cause of cancer. For example, over-expression of hyper-activation of many PTKases are oncogenic. The signals that are transmitted by PTKases must be counterbalanced by the action of protein tyrosine phosphatases (PTPases). Thus, the roles of PTPases in cell regulation must also be studied to understand the generation of cancer, and to develop rational cancer treatments. Although a rapid progress is being made on the structural and biochemical properties of PTPases, their physiological roles and regulations are not yet clearly understood. This proposal aims to fill this gap in our knowledge by studying the human transmembrane PTPase LAR and its Drosophila homolog DLAR. Aim 1. Characterization of ligands for DLAR and LAP PTPases. In preliminary studies, it was found that the three Ig-domains of DLAR is functionally important. Two potential ligand proteins that bind the DLAR Ig-domains have been identified using yeast two-hybrid method. In this project, the complete coding sequences of these putative ligands will be cloned and their properties will be characterized both biochemically and functionally. Also, ligand(s) of the human LAR PTPase will be identified are studied. Aim 2. Characterization of Drosophila DLAR PTPase, as a model genetic system for receptor-PTPases. In this project, the DLAR function will be dissected using P-element transformation. Also, other signaling elements in the DLAR signal transduction pathway will be identified by genetic suppressor mutant isolation. Aim 3. Crystallographic studies on the structures of the LAR and CD45 PTPase domains. The structural determination of the human LAR PTPase will be determined. The structures of phosphatase-substrate complexes will be determined. Also, the structural basis of the catalytic and regulatory functions of the individual PTPase domains in LAR will be investigated.